20-61928394-G-C

Position:

• chr20-61928394-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_001794.5(CDH4):​c.1976G>C​(p.Arg659Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDH4 NM_001794.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.77

Genes affected

CDH4 (HGNC:1763): (cadherin 4) This gene is a classical cadherin from the cadherin superfamily. The encoded protein is a calcium-dependent cell-cell adhesion glycoprotein comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Based on studies in chicken and mouse, this cadherin is thought to play an important role during brain segmentation and neuronal outgrowth. In addition, a role in kidney and muscle development is indicated. Of particular interest are studies showing stable cis-heterodimers of cadherins 2 and 4 in cotransfected cell lines. Previously thought to interact in an exclusively homophilic manner, this is the first evidence of cadherin heterodimerization. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 20-61928394-G-C is Pathogenic according to our data. Variant chr20-61928394-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402151.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr20-61928394-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH4	NM_001794.5	c.1976G>C	p.Arg659Pro	missense_variant	12/16	ENST00000614565.5	NP_001785.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH4	ENST00000614565.5	c.1976G>C	p.Arg659Pro	missense_variant	12/16	1	NM_001794.5	ENSP00000484928.1
CDH4	ENST00000543233.2	c.1754G>C	p.Arg585Pro	missense_variant	11/15	2		ENSP00000443301.1
CDH4	ENST00000611855.4	c.1694G>C	p.Arg565Pro	missense_variant	11/15	5		ENSP00000480844.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459568 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Abnormal brain morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.7	.;.;D
REVEL	Uncertain	0.40
Sift	Benign	0.049	.;.;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.73
MutPred		0.49		Loss of MoRF binding (P = 0.0077);.;.;
MVP		0.82
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.72
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs765815715; hg19: chr20-60503452;